Michinori Ogura1, Juan Manuel Sancho2, Seok-Goo Cho3, Hideyuki Nakazawa4, Junji Suzumiya5, Gayane Tumyan6, Jin Seok Kim7, Anne Lennard8, José Mariz9, Nikolai Ilyin10, Wojciech Jurczak11, Aurelio Lopez Martinez12, Olga Samoilova13, Edvard Zhavrid14, Eduardo Yañez Ruiz15, Marek Trneny16, Leslie Popplewell17, Bertrand Coiffier18, Christian Buske19, Won-Seog Kim20, Sang Joon Lee21, Sung Young Lee21, Yun Ju Bae21, Larry W Kwak22. 1. Department of Haematology and Oncology, Kasugai Municipal Hospital, Kasugai, Japan; School of Medicine, Fujita Medical University, Toyoake, Japan. 2. Hematology Department, The Catalan Institute of Oncology-The Josep Carreras Leukaemia Research Institute, Hospital Germans Trias i Pujol, Badalona, Spain. 3. Department of Hematology, Catholic Blood and Marrow Transplantation Center, Seoul St Mary's Hospital, The Catholic University of Korea, Seoul, South Korea. 4. Department of Hematology, Shinshu University School of Medicine, Matsumoto, Japan. 5. Shimane University Hospital, Innovative Cancer Center/Oncology-Hematology, Izumo, Japan. 6. Division of Hematology and Bone Marrow Transplantation, N N Blokhin Russian Cancer Research Center, Moscow, Russia. 7. Department of Internal Medicine, Yonsei University College of Medicine, Severance Hospital, Seoul, South Korea. 8. Northern Institute for Cancer Care, Newcastle University, Newcastle-upon-Tyne, UK. 9. Department of Onco-Hematology, Portuguese Institute of Oncology, Porto, Portugal. 10. Russian Research Center for Radiology and Surgical Technologies, Ministry of Health of the Russian Federation, St Petersburg, Russia. 11. Department of Haematology, Jagiellonian University, Kraków, Poland. 12. Department of Hematology, Hospital Arnau de Vilanova, Valencia, Spain. 13. Department of Hematology, Nizhniy Novgorod Region Clinical Hospital, Nizhniy Novgorod, Russia. 14. N N Alexandrov Republican Scientific and Practical Centre of Oncology and Medical Radiology, Minsk, Belarus. 15. Department of Internal Medicine, Universidad de la Frontera, Temuco, Chile. 16. Department of Medicine, Charles University, General Hospital in Prague, Prague, Czech Republic. 17. Toni Stephenson Lymphoma Center and Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA. 18. Department of Hematology, Hospices Civils de Lyon, Lyon, France. 19. Comprehensive Cancer Center Ulm, University Hospital of Ulm, Ulm, Germany. 20. Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. 21. Celltrion, Inc., Incheon, South Korea. 22. Toni Stephenson Lymphoma Center and Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA. Electronic address: lkwak@fsm.northwestern.edu.
Abstract
BACKGROUND: Studies in patients with rheumatoid arthritis and advanced follicular lymphoma have shown that CT-P10, a rituximab biosimilar, has equivalent or non-inferior efficacy and pharmacokinetics to rituximab. We aimed to assess the therapeutic equivalence of single-agent CT-P10 and rituximab in patients with newly diagnosed low-tumour burden follicular lymphoma. METHODS: In this ongoing, randomised, double-blind, parallel-group, active-controlled, phase 3 trial, adult patients (≥18 years) with stage II-IV low-tumour-burden follicular lymphoma were randomly assigned (1:1) using an interactive web or voice response system stratified by region, stage, and age to CT-P10 or US-sourced rituximab. Patients received CT-P10 or rituximab (375 mg/m2 intravenous) on day 1 of four 7-day cycles (induction period). Patients who had disease control after the induction period continued to a maintenance period ofCT-P10 or rituximab administered every 8 weeks for six cycles and, if completed, a second year of maintenance therapy of additional CT-P10 (every 8 weeks for six cycles) was offered. The study was partially unmasked after database lock (Feb 23, 2018) for all data up to 7 months (before cycle 3 of the maintenance period). The primary endpoint was the proportion of patients who achieved an overall response by 7 months in the intention-to-treat population. Efficacy equivalence was shown if the two-sided 90% CIs for the treatment difference in the proportion of responders between CT-P10 and rituximab was within the equivalence margin of 17%. This trial is registered with ClinicalTrials.gov, number NCT02260804. FINDINGS:Between Nov 9, 2015, and Jan 4, 2018, 402 patients were assessed for eligibility, of whom 258 were randomly assigned: 130 to CT-P10 and 128 torituximab. 108 (83%) of 130 patients assigned to CT-P10 and 104 (81%) of 128 assigned to rituximab achieved an overall response by month 7 (treatment difference estimate 1·8%; 90% CI -6·43 to 10·20). Therapeutic equivalence was shown (90% CIs were within the prespecified margin of 17%). The most common grade 3 or 4 treatment-emergent adverse events were decreased neutrophil count (two grade 3 in the CT-P10 group) and neutropenia (one in each group); all other grade 3 or 4 treatment-emergent adverse events occurred in one patient each. Six (5%) of 130 patients who received CT-P10 and three (2%) of 128 who received rituximab experienced at least one treatment-emergent serious adverse event. INTERPRETATION: CT-P10 was equivalent to rituximab in terms of efficacy and was well tolerated. CT-P10 monotherapy is suggested as a new therapeutic option for patients with low-tumour-burden follicular lymphoma. FUNDING: Celltrion, Inc.
RCT Entities:
BACKGROUND: Studies in patients with rheumatoid arthritis and advanced follicular lymphoma have shown that CT-P10, a rituximab biosimilar, has equivalent or non-inferior efficacy and pharmacokinetics to rituximab. We aimed to assess the therapeutic equivalence of single-agent CT-P10 and rituximab in patients with newly diagnosed low-tumour burden follicular lymphoma. METHODS: In this ongoing, randomised, double-blind, parallel-group, active-controlled, phase 3 trial, adult patients (≥18 years) with stage II-IV low-tumour-burden follicular lymphoma were randomly assigned (1:1) using an interactive web or voice response system stratified by region, stage, and age to CT-P10 or US-sourced rituximab. Patients received CT-P10 or rituximab (375 mg/m2 intravenous) on day 1 of four 7-day cycles (induction period). Patients who had disease control after the induction period continued to a maintenance period of CT-P10 or rituximab administered every 8 weeks for six cycles and, if completed, a second year of maintenance therapy of additional CT-P10 (every 8 weeks for six cycles) was offered. The study was partially unmasked after database lock (Feb 23, 2018) for all data up to 7 months (before cycle 3 of the maintenance period). The primary endpoint was the proportion of patients who achieved an overall response by 7 months in the intention-to-treat population. Efficacy equivalence was shown if the two-sided 90% CIs for the treatment difference in the proportion of responders between CT-P10 and rituximab was within the equivalence margin of 17%. This trial is registered with ClinicalTrials.gov, number NCT02260804. FINDINGS: Between Nov 9, 2015, and Jan 4, 2018, 402 patients were assessed for eligibility, of whom 258 were randomly assigned: 130 to CT-P10 and 128 to rituximab. 108 (83%) of 130 patients assigned to CT-P10 and 104 (81%) of 128 assigned to rituximab achieved an overall response by month 7 (treatment difference estimate 1·8%; 90% CI -6·43 to 10·20). Therapeutic equivalence was shown (90% CIs were within the prespecified margin of 17%). The most common grade 3 or 4 treatment-emergent adverse events were decreased neutrophil count (two grade 3 in the CT-P10 group) and neutropenia (one in each group); all other grade 3 or 4 treatment-emergent adverse events occurred in one patient each. Six (5%) of 130 patients who received CT-P10 and three (2%) of 128 who received rituximab experienced at least one treatment-emergent serious adverse event. INTERPRETATION:CT-P10 was equivalent to rituximab in terms of efficacy and was well tolerated. CT-P10 monotherapy is suggested as a new therapeutic option for patients with low-tumour-burden follicular lymphoma. FUNDING: Celltrion, Inc.
Authors: Pier Luigi Zinzani; Martin Dreyling; William Gradishar; Marc Andre; Francisco J Esteva; Suliman Boulos; Eva González Barca; Giuseppe Curigliano Journal: Drugs Date: 2019-10 Impact factor: 9.546